The Indian Patent Office on April 1, 2016 denied Cipla
(Applicant) limited a patent for its HIV drug comprising
"ritonavir" and "darunavir"
involving the patent application 1399/MUMNP/2010
entitled, "Antiretroviral Combination".
The IPO rejected the Patent Application on the grounds of lack of
inventive step in view of the prior published documents as well as
on basis of Section 3(d) of the Patents Act.

BRIEF BACKGROUND

Cipla Limited filed Indian patent application 1399/
MUMNP/2010 entitled "Anti-retroviral
Combination" in the Indian Patent Office (IPO) on
June 30, 2010. The '1399 application describes a pharmaceutical
composition comprising of ritonavir and darunavir for treating HIV
or AIDS. The application was filed with 22 claims. A request for
examination was filed for the '1399 application on November 22,
2011, and a first examination report was issued on October 27,
2014. In the examination report, all twenty-two claims were found
to lack novelty and inventive step over the prior art.

According to the examiner, D1 discloses a single solid dosage
comprising of darunavir, tipranavir and optionally ritonavir. D2
discloses an anti-HIV combination comprising tenofovir or its
disoproxil fumarate derivative, ritonavir and TMC 114(darunavir)
useful for the treatment or prevention of HIV infections.
Considering D1 and D2, the claims 1, 8, 10, 12 and 22 of the
present invention lacked novelty in view of the examiner.

D3 discloses the co-administration of ritonavir and darunavir
for the treatment of HIV. Though D3 does not disclose a bi-layer
tablet or the use of a polymer as excipient but only refers to the
combined application of drugs. D4 and D5 mention that
pharmaceutical compositions comprising one or more HIV protease
inhibitor can be prepared in form of bi-layer tablets with a
polymer as excipient.

The examiners in view of the aforementioned disclosures declared
that it would have been obvious for any skilled person to combine
the teachings of D3 with that of D4 and D5 to arrive at the present
invention. Therefore the claims 1 to 22 were rejected due to lack
of inventive step and do not constitute an invention u/s 2(1)(j) of
the Patents Act 1970.Further the examiner pointed that Claims 10
and 22 are use claims, which are not permissible
u/s 2(1)(j) of the Act. Claim 12 is directed to methods of
treatments which are barred from being patentable u/s 3(i) of the
Indian Patents Act.

The applicant filed a response with amended claims. In response
to the examination report, the Applicant argued that the
counterpart European Patent (EP2242482 B1) had been issued after
taking into consideration all of the cited documents listed above
(excluding D2), and after the insertion of the limitation of
original claim 2 into original claim 1, such that the new
independent Indian claim read like the granted claim in the
corresponding European application:

"1. A pharmaceutical composition comprising a solid dosage
form comprising:

(i) ritonavir or a pharmaceutically acceptable salt and ester
thereof;

(ii) darunavir or a pharmaceutically acceptable salt and ester
thereof;

(iii) Optionally, at least one pharmaceutically
acceptable excipient, which composition is a tablet formulation
comprising said ritonavir in a first layer of the formulation and
said darunavir in a second layer of the
formulation."

APPLICANT'S ARGUMENTS

The applicant argued that the present invention relates to a
solid, unit dosage form comprising ritonavir in a first layer and
darunavir in the second layer. The applicant submitted that none of
the cited prior art documents disclosed such dosage forms hence
there exist a novelty. Further, the applicant identified that D3 is
the closest cited prior whose teachings were directed to a clinical
trial involving administering the combination of darunavir and
ritonavir, thereby supervising the administration of actives. The
applicant argued that though HIV protease inhibitors taken in
combination with cytochrome P450 inhibitors such as ritonavir and
darunavir have improved pharmacokinetics as compared to taking HIV
protease inhibitors alone, it becomes impractical to supervise the
administration of active compounds involving different dosage
schedules. Such administration and supervision would result in an
increase of "pill burden" and poor patient
compliance.

It was further argued by the Applicant that in order to overcome
the above said, the present invention provided a single unit dosage
form comprising darunavir and ritonavir that simplify the dosage
schedule and decreases the 'pill burden'.

The Applicant
submitted that D1 and D2 do not provide any further information
regarding the incompatibility of ritonavir and darunavir. D4 and D5
describe multilayer forms that allow the combination of active
ingredients which are otherwise non-compatible and require separate
processing steps.

After the receipt of response for FER, the patent office further
conducted an extensive examination and found that the response did
not comply with the objections raised in the examination report.
The Patent Office scheduled a hearing on 19th February 2016, and
issued a letter citing an additional prior art reference,
D6 (US 2005/0048112).

MOTIVATION FOR THE INGREDIENTS OF THE FORMULATION AS WELL AS
THE MULTILAYER DOSAGE FORM BASED ON D6

According to the examiner D6 disclose solid pharmaceutical forms
comprising of ritonavir and optionally comprises of second species
of HIV protease inhibitor. It was further identified that D6
mention 24 species of HIV protease inhibitor other than ritonavir,
including TMC-114(darunavir). Therefore D6 provide a strong
motivation to formulate a solid pharmaceutical dosage form that
comprises of both ritonavir and darunavir. The examiner pointed
that D6 additionally discloses that the solid pharmaceutical dosage
form comprises "at least one pharmaceutically acceptable
water-soluble polymer".

D6 further discuss that "dosage forms according to the
invention may be provided as dosage forms consisting of several
layers for example laminated or multilayer tablets. It is mentioned
in D6 that "it is possible to provide an initial dose by
including an active ingredient in one of the outer layers, and a
maintenance dose by including the active ingredient in the inner
layers.

After analyzing the reply submissions of the Applicant, the
Controller maintained that the claimed subject matter did not
clearly show an advantage or surprising effect over the prior art.
In addition, the Controller argued that the claims in the present
application related to a new layered form of a known combination of
the prior art, and thus were not patentable under Section 3(d) of
the Patents Act. Section 3(d) reads "the mere discovery of any
new property or new use for a known substance or of the mere use of
a known process, machine, or apparatus, unless such known process
results in a new product or employs at least one new reactant"
does not constitute a patentable invention. Further the
Controller specifically pointed that only the therapeutic effect of
the compounds in question, are relevant in assessing the inventive
step and patentability under section 3(d) and not the physical
properties of the compounds.

THE APPLICANT'S POST HEARING SUBMISSIONS

Post hearing, the Applicant submitted a written reply and
amended the claims. The Applicant argued that the prior art
disclosures (D4, D5 and D6) did not disclose the specific
combination of ritonavir and darunavir, and that the combination of
ritonavir and darunavir in separate layers of a single composition
was new. The Applicant strongly focused on the data that showed the
mixing ritonavir and darunavir in the same layer adversely affect
the release of both active compounds which was overcome in the
present invention by providing the two active compounds in separate
layers. Such an arrangement provided for an optimal dissolution
profiles for both the actives. The Applicant mentioned that neither
D3 nor any of the other cited prior art suggested for improving the
dissolution profile for the combination of darunavir and ritonavir,
in a multilayer form, having the active compounds in separate
layers so as to result in the optimal release profile of the
separate drugs.

The amended new claim is as follows,

A pharmaceutical composition comprising a solid dosage form
comprising:

(i) ritonavir or a pharmaceutically acceptable salt and ester
thereof;

(ii) darunavir or a pharmaceutically acceptable salt and ester
thereof;

(iii) a water insoluble polymer and/or a water soluble polymer,
wherein the ratio of the weight of the ritonavir or darunavir to
the weight of the polymer is from 1:1 to 1:6;

(iv) Optionally at least one pharmaceutically acceptable
excipient, which composition is a tablet formulation comprising
said ritonavir and said polymer in a first layer of the formulation
and said darunavir in a second layer of the formulation; wherein
the first layer is obtainable by hot melt extruding, and the second
layer is obtainable by direct compression or by wet
granulation."

CONTROLLER'S DECISION

The Objections pertaining to inventive step and section 3(d) was
maintained by the controller. With regards to D6 the Controller
observed that "dosage forms according to the invention may be
provided as dosage forms consisting of several layers, for example
laminated or multilayer tablets. Further multilayer forms have the
advantage that the two active ingredients which are incompatible
with one another can be processed, or that the release
characteristics of the active ingredient(s) can be
controlled".

It was specifically mentioned in D6 that "it is possible to
provide an initial dose by including an active ingredient in one of
the outer layers, and a maintenance dose by including the active
ingredient in the inner layer(s)".

In view of the above the controller rejected the Applicant's
reply submissions considering D1-D5 and D6, composition comprising
darunavir and ritonavir and its use known from D1-D6. Further
claimed subject matter did not clearly exhibit advantage/surprising
effect over the prior art composition.

CONCLUSION:

The claim of the present invention consider the new layered form
of a known combination of prior art, which are not considered as
being patentable under Section 3(d) of the Indian Patents Act.
Therefore the subject matter of claims 1-8 were rejected as it
falls under Section 3(d) of the Act. Also, in view of the aforesaid
disclosures, it would have been obvious for a person skilled in the
art to combine the teachings of D3 with that of D4 or D5-D6. Hence
the claims 1-8 lack inventive step and do not constitute invention
under section 2(1) (j) of the Indian Patents Act, 1970.

The Patents Act 1970, along with the Patents Rules 1972, came into force on 20th April 1972, replacing the Indian Patents and Designs Act 1911. The Patents Act was largely based on the recommendations of the Ayyangar Committee Report headed by Justice N. Rajagopala Ayyangar. One of the recommendations was the allowance of only process patents with regard to inventions relating to drugs, medicines, food and chemicals.

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